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The enzyme ATE1 catalyzes eukaryotic post-translation arginylation, a key protein modification necessary for cellular homeostasis. Here, the authors show that ATE1s are previously unrealized iron-sulfur proteins that use this oxygen-sensitive inorganic cofactor to control cellular arginylation

Jetted active galactic nuclei (AGN) hosting extended photoionized nebulae provide us with a unique view of the timescales associated with AGN activity. Here, we present a new green bean galaxy at z = 0.304458 ± 0.000007 with large-scale jet-induced radio emission. The spectral energy distributions of the radio components show steep spectral indices ( α = −0.85 to −0.92 for the extended regions, and α = −1.02 for the faint radio core), and spectral age modeling of the extended radio emission indicates that the lobes are >6 Myr old. It is unclear whether the jet is active, or is a remnant with an off-time of 2–3 Myr. Several detached clouds lie around the host galaxy up to 37.8 kpc away from the nucleus, and their ionization profile indicates a decline (∼2 dex) in the AGN ionizing photon production over the past ∼0.15 Myr. Furthermore, we measure a blueshift for one of the clouds that is spatially coincident with the path of the radio jet. The cloud is likely illuminated by the photoionizing AGN, and potentially underwent an interaction with the relativistic jet. Our multiwavelength analysis suggests that RGB1 was in a phase of jet production prior to the radiatively efficient accretion phase traced by the detached cloud emission. It is unclear whether RGB1 transitioned into a low-excitation radio galaxy or an inactive galaxy over the past ∼0.15 Myr, or whether the extended radio and optical emission trace distinct accretion phases that occurred in succession.

The amounts of the intracellular glycosylation, O-GlcNAc modification, are increased in essentially all tumors when compared to healthy tissue, and lowering O-GlcNAcylation levels results in reduced tumorigenesis and increased cancer cell death. Therefore, the pharmacological reduction of O-GlcNAc may represent a therapeutic vulnerability. The most direct approach to this goal is the inhibition of O-GlcNAc transferase (OGT), the enzyme that directly adds the modification to proteins. However, despite some recent success, this enzyme has proven difficult to inhibit. An alternative strategy involves starving OGT of its sugar substrate UDP-GlcNAc by targeting enzymes of the hexosamine biosynthetic pathway (HBP). Here, we explore the potential of the rate-determining enzyme of this pathway, glutamine fructose-6-phosphate amidotransferase (GFAT). We first show that CRISPR-mediated knockout of GFAT results in inhibition of cancer cell growth in vitro and a xenograft model that correlates with O-GlcNAcylation levels. We then demonstrate that pharmacological inhibition of GFAT sensitizes a small panel of cancer cells to undergo apoptosis in response to diamide-induced oxidative stress. Finally, we find that GFAT expression and O-GlcNAc levels are increased in a spontaneous mouse model of liver cancer. Together these experiments support the further development of inhibitors of the HBP as an indirect approach to lowering O-GlcNAcylation levels in cancer.

It is challenging to biosynthesize industrially important aldehydes, which are readily consumed by the numerous alcohol dehydrogenases (ADHs) in cells. In this work, we demonstrate that a nicotinamide mononucleotide (NMN+)-dependent redox cofactor cycling system enables aldehyde accumulation in Escherichia coli crude lysates and whole cells. By specifically delivering reducing power to a recombinant enoate reductase, but not to endogenous ADHs, we convert citral to citronellal with minimal byproduct formation (97-100% and 83% product purity in crude lysate- and whole cell-based biotransformation, respectively). We envision the system's universal application to lowering the noise in biomanufacturing by silencing the host's metabolic background.

Perceptual learning (PL), often characterized by improvements in perceptual performance with training that are specific to the stimulus conditions used during training, exemplifies experience-dependent cortical plasticity. An improved understanding of how neuromodulatory systems shape PL promises to provide new insights into the mechanisms of plasticity, and by extension how PL can be generated and applied most efficiently. Previous studies have reported enhanced PL in human subjects following administration of drugs that increase signaling through acetylcholine (ACh) receptors, and physiological evidence indicates that ACh sharpens neuronal selectivity, suggesting that this neuromodulator supports PL and its stimulus specificity. Here we explored the effects of enhancing endogenous cholinergic signaling during PL of a visual texture discrimination task. We found that training on this task in the lower visual field yielded significant behavioral improvement at the trained location. However, a single dose of the cholinesterase inhibitor donepezil, administered before training, did not significantly impact either the magnitude or the location specificity of texture discrimination learning compared with placebo. We discuss potential explanations for discrepant findings in the literature regarding the role of ACh in visual PL, including possible differences in plasticity mechanisms in the dorsal and ventral cortical processing streams.

Abstract Background A central challenge in preclinical research investigating the biology of autism spectrum disorder (ASD) is the translation of ASD-related social phenotypes across humans and animal models. Social orienting, an observable, evolutionarily conserved behavior, represents a promising cross-species ASD phenotype given that disrupted social orienting is an early-emerging ASD feature with evidence for predicting familial recurrence. Here, we adapt a competing-stimulus social orienting task from domesticated dogs to naturalistic play behavior in human toddlers and test whether this approach indexes decreased social orienting in ASD. Methods Play behavior was coded from the Autism Diagnostic Observation Schedule (ADOS) in two samples of toddlers, each with and without ASD. Sample 1 (n = 16) consisted of community-ascertained research participants, while Sample 2 involved a prospective study of infants at a high or low familial liability for ASD (n = 67). Coding quantified the child’s looks towards the experimenter and caregiver, a social stimulus, while playing with high-interest toys, a non-social stimulus. A competing-stimulus measure of “Social Attention During Object Engagement” (SADOE) was calculated by dividing the number of social looks by total time spent playing with toys. SADOE was compared based on ASD diagnosis and differing familial liability for ASD. Results In both samples, toddlers with ASD exhibited significantly lower SADOE compared to toddlers without ASD, with large effect sizes (Hedges’ g ≥ 0.92) driven by a lower frequency of child-initiated spontaneous looks. Among toddlers at high familial likelihood of ASD, toddlers with ASD showed lower SADOE than toddlers without ASD, while SADOE did not differ based on presence or absence of familial ASD risk alone. SADOE correlated negatively with ADOS social affect calibrated severity scores and positively with the Communication and Symbolic Behavior Scales social subscale. In a binary logistic regression model, SADOE alone correctly classified 74.1% of cases, which rose to 85.2% when combined with cognitive development. Conclusions This work suggests that a brief behavioral measure pitting a high-interest nonsocial stimulus against the innate draw of social partners can serve as a feasible cross-species measure of social orienting, with implications for genetically informative behavioral phenotyping of social deficits in ASD and other neurodevelopmental disorders.

Abstract Tinnitus, or ringing in the ears, is a prevalent condition that imposes a substantial health and financial burden on the patient and to society. The diagnosis of tinnitus, like pain, relies on patient self-report, which can complicate the distinction between actual and fraudulent claims. Here, we combined tablet-based self-directed hearing assessments with neural network classifiers to automatically differentiate participants with tinnitus (N = 24) from a malingering cohort, who were instructed to feign an imagined tinnitus percept (N = 28). We identified clear differences between the groups, both in their overt reporting of tinnitus features, but also covert differences in their fingertip movement trajectories on the tablet surface as they performed the reporting assay. Using only 10 min of data, we achieved 81% accuracy classifying patients and malingerers (ROC AUC = 0.88) with leave-one-out cross validation. Quantitative, automated measurements of tinnitus salience could improve clinical outcome assays and more accurately determine tinnitus incidence.

Purpose: This review article provides a theoretical overview of the development of spectral resolution in children with normal hearing (cNH) and in those who use cochlear implants (CIs), with an emphasis on methodological considerations. The aim was to identify key directions for future research on spectral resolution development in children with CIs. Method: A comprehensive literature review was conducted to summarize and synthesize previously published behavioral research on spectral resolution development in normal and impaired auditory systems. Conclusions: In cNH, performance on spectral resolution tasks continues to improve through the teenage years and is likely driven by gradual maturation of across-channel intensity resolution. A small but growing body of evidence from children with CIs suggests a more complex relationship between spectral resolution development, patient demographics, and the quality of the CI electrode--neuron interface. Future research should aim to distinguish between the effects of patient-specific variables and the underlying physiology on spectral resolution abilities in children of all ages who are hard of hearing and use auditory prostheses., Accurate discrimination of speech sounds, especially in adverse listening conditions, relies on the ability to resolve spectral components of complex acoustic signals. In children with a typically developing auditory system, [...]

Background: The risk of death after a postoperative complication--known as failure to rescue (FTR)--has been proposed to be superior to traditional benchmarking outcomes, such as complication and mortality rates, as a measure of system quality. The purpose of this study was to identify the current FTR rate in emergency general surgery (EGS) centres across Canada. We hypothesized that substantial variability exists in FTR rates across centres. Methods: In this multicentre retrospective cohort study, we performed a secondary analysis of data from a previous study designed to evaluate operative intervention for nonappendiceal, nonbiliary disease by 6 EGS services across Canada (1 in British Columbia, 1 in Alberta, 3 in Ontario and 1 in Nova Scotia). Patients underwent surgery between Jan. 1 and Dec. 31, 2014. We conducted univariate analyses to compare patients with and without complications. We performed a sensitivity analysis examining the mortality rate after serious complications (Clavien-Dindo score 3 or 4) that required a surgical intervention or specialized care (e.g., admission to intensive care unit). Results: A total of 2595 patients were included in the study cohort. Of the 206 patients who died within 30 days, 145 (70.4%) experienced a complication before their death. Overall, the mortality rate after any surgical complication (i.e., FTR) was 16.0%. Ranking of sites by the traditional outcomes of complication and mortality rates differed from the ranking when FTR rate was included in the assessment. Conclusion: There was variability in FTR rates across EGS services in Canada, which suggests that there is opportunity for ongoing quality-improvement efforts. This study provides FTR benchmarking data for Canadian EGS services. Contexte : On a propose que le risque de deces apres une complication postoperatoire--appele << echec de sauvetage >>--pourrait s'averer une mesure plus pertinente de la qualite du systeme de sante que les indicateurs comparatifs traditionnels, comme les taux de complications et de mortalite. Cette etude visait a determiner le taux reel d'echec de sauvetage dans les centres de chirurgies generales d'urgence (CGU) au Canada. Notre hypothese etait que ce taux varie grandement d'un centre a l'autre. Methodes : Dans le cadre de cette etude de cohorte retrospective multicentrique, nous avons realise une analyse secondaire des donnees issues d'une etude anterieure, dont l'objectif etait d'evaluer les interventions chirurgicales relatives a des atteintes ne touchant ni l'appendice ni la vesicule biliaire effectuees par 6 centres de CGU au Canada (1 en Colombie-Britannique, 1 en Alberta, 3 en Ontario et 1 en Nouvelle-Ecosse). Ces interventions ont eu lieu du 1er janvier au 31 decembre 2014. Nous avons compare les 2 categories de patients--avec complications et sans complications--au moyen d'analyses univariees. Nous avons aussi mene une analyse de sensibilite con-cernant le taux de mortalite apres des complications graves (3 ou 4 selon la classification de Clavien-Dindo) qui ont necessite une intervention chirurgicale ou des soins specialises (par exemple, une admission en soins intensifs). Resultats : L'etude a porte sur un total de 2595 patients. Sur les 206 patients decedes dans les 30 jours, 145 (70,4 %) ont eu une complication avant leur deces. Globalement, le taux de mortalite apres une complication postoperatoire (soit le taux d'echec de sauvetage) etait de 16,0 %. Le classement des centres avec les indicateurs traditionnels (taux de complications et de mortalite) n'etait pas le meme une fois pris en compte le taux d'echec de sauvetage. Conclusion : Le taux d'echec de sauvetage varie d'un centre de CGU a l'autre au pays, ce qui laisse croire qu'une amelioration continue de la qualite reste possible. Cette etude fournit des donnees de reference sur les taux d'echec de sauvetage aux centres de CGU au Canada., Emergency general surgery (EGS) conditions present a substantial health care burden, accounting for 7% of all hospital admissions in the United States. (1) About 25% of patients admitted with an [...]

We examined the relations of restricted and repetitive behaviors (RRB; insistence on sameness, repetitive sensory-motor, self-injurious behavior) to social skills overall and aspects that comprise social skills as measured by the VABS-II (coping skills, play/leisure time, interpersonal relationships) in 24- (n = 63) and 36-month old (n = 35), high-familial-risk toddlers with ASD. Hierarchical linear regression results indicated that repetitive sensory-motor was the best predictor of social skills overall. Secondary results indicated that all three RRB subtypes were associated with each subdomain of social skills; however, repetitive sensory-motor was the strongest and most consistent among these effects. While our results suggests a general negative relation of subtypes of RRB to aspects of adaptive social function, repetitive sensory-motor behaviors may be of particular relevance to the development of social skills during toddlerhood., Author(s): Pang Chaxiong [sup.1] , Catherine Burrows [sup.1] , Kelly N. Botteron [sup.2] , Stephen R. Dager [sup.3] , Annette M. Estes [sup.3] , Heather C. Hazlett [sup.4] , Robert [...]

ABSTRACT This learning activity teaches the difficult concept of V(D)J recombination as it occurs in B cells. Following the traditional lecture, this hands-on activity uses pipe cleaners of various colors representing variable, joining, and diversity gene segments and recombination signal sequences. Students are provided with instructions for using the pipe cleaners to assemble specific light and heavy immunoglobulin chains. Students each assemble their own light and heavy chains and compare the products made by classmates. This activity uses materials that are easy and affordable to acquire and provides a tactile approach to reinforcing concepts that students often struggle to visualize and master from lecture and textbook material alone.

AimTo describe patients’ reported employment challenges associated with diabetic foot ulcers (DFUs).MethodsFifteen patients from under-resourced communities in Southern Arizona, with a history of DFUs and/or amputations, were recruited from a tertiary referral center from June 2020 to February 2021. Participants consented to an audio-recorded semi-structured phone interview. Interviews were transcribed and thematically analyzed using the Dedoose data analysis platform.ResultsParticipants shared a common theme around the cyclic challenges of DFU prevention/management and employment. Those employed in manual labor-intensive jobs or jobs requiring them to be on their feet for long durations of time believed working conditions contributed to the development of their DFUs. Patients reported work incapacity due to declines in mobility and the need to offload for DFU management. Many expressed frustration and emotional distress related to these challenges noting that DFUs resulted in lower remuneration as medical expenses increased. Consequently, loss of income and/or medical insurance often hindered participants’ ability to manage DFUs and subsequent complications.ConclusionThese data illuminate the vicious cycle of DFU and employment challenges that must be addressed through patient-centered prevention strategies. Healthcare providers should consider a person’s contextual factors such as employment type to tailor treatment approaches. Employers should establish inclusive policies that support patients with DFUs returning to work through flexible working hours and adapted work tasks as needed. Policymakers can also mitigate employment challenges by implementing social programs that provide resources for employees who are unable to return to work in their former capacity.

The effects of synthetic, free-amino acid diets, similar to those prescribed as supplements for (phenylketonuria) PKU patients, on gut microbiota and overall health are not well understood. In the current, multidisciplinary study, we examined the effects of a synthetically-derived, low-fiber, amino acid diet on behavior, cognition, gut microbiome composition, and inflammatory markers. A cohort of 20 male C57BL/6J mice were randomly assigned to either a standard or synthetic diet (n = 10) at post-natal day 21 and maintained for 13 weeks. Sequencing of the 16S rRNA gene from fecal samples revealed decreased bacterial diversity, increased abundance of bacteria associated with disease, such as Prevotella, and a downward shift in gut microbiota associated with fermentation pathways in the synthetic diet group. Furthermore, there were decreased levels of short chain fatty acids and shortening of the colon in mice consuming the synthetic diet. Finally, we measured TNF-α, IL-6, and IL-10 in serum, the hippocampus, and colon, and found that the synthetic diet significantly increased IL-6 production in the hippocampus. These results demonstrate the importance of a multidisciplinary approach to future diet and microbiome studies, as diet not only impacts the gut microbiome composition but potentially systemic health as well.